Pharmacokinetics and Pharmacodynamics of Fluconazole in a Murine Model of Cryptococcal Meningitis With Bridging to Humans: High Dosages are Required for Near-Maximal Antifungal Activity

Ref ID: 18716

Author:

A. Sudan, MD – Research Fellow, J. Livermore, PhD – Research Assistant, S. Howard, PhD – Research Associate, Z. Al-Nakeeb, MD – Research Fellow, A. Sharp, BSc – Research Assistant, J. Goodwin, BSc – Research Assistant, L. Gregson, MSc – Research Assi

Author address:

The Univ. of Manchester, Manchester, United Kingdom.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Cryptococcal meningitis causes 600,000 deaths/yr. Administration of a standard i.v. induction regimen is often infeasible in the developing world. An oral induction agent would be beneficial, but there is uncertainty regarding the optimal regimen. We defined the PK-PD for fluconazole against Cryptococcus neoformans and bridged the results from mice to humans. Methods: Four isolates of C. neoformans were studied (HA99, F6137, F13186, F20886). Mice were inoculated i.v. Oral fluconazole was administered on day 1, and then every 24 hours for 10 days. Mice (n=3) received either 125 mg/kg/day or 250 mg/kg/day. A control group received vehicle only. Fluconazole concentrations were determined by HPLC in plasma and cerebrum. Fungal burden was quantified in the brain by culture. A 5-compartment mathematical model was used to link cerebral drug exposure and antifungal effect. This model was used to define the drug exposure associated with near-maximal antifungal activity. The results were bridged to humans to identify a clinical regimen associated with near-maximal antifungal activity. Results: All strains grew logarithmically. The PK were linear, with no evidence of hysteresis. Fluconazole resulted in a dose-dependent decline in cerebral fungal burden. The mathematical model readily accounted for the PK and PD data. An AUC of [[Unable to Display Character: 61566;]]1600 mg.h/L was associated with a 3 log drop in CFU/g brain. The PK-PD bridging study suggested that human dosages of ≥ 1200 mg/day are associated with near-maximal antifungal activity. Conclusions: This study provides the experimental basis for further clinical studies attempting to identify optimal fluconazole regimens. Current fluconazole regimens of 400-800 mg/day result in sub-maximal antifungal effect. Dosages of ≥ 1200 mg/day are required to achieve near-maximal antifungal activity.

Abstract Number: A-1943

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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